Tiny particles with a big future. From cancer treatment to space!

Nanoparticles technology is a fascinating technology with many potential applications. The collaboration between The University of Sydney's Key Centre for Polymers and Colloids and Sirtex Medical Ltd is investigating possible applications for chemotherapy treatments in solid tumours as well as navigational thrusters for mini satellites in space.

The University of Sydney’s Key Centre for Polymers and Colloids (KCPC) initially exchanged confidential agreements with Sirtex in 2001 and we discussed a variety of projects that we might do together. Our work together started in earnest in 2003, when we simultaneously commenced two projects, one on the provision of an alternative method for making SIR-Spheres microspheres and the other on designing and making hyperthermia beads. The SIR-Spheres microspheres project was successful in using a process called membrane emulsification to make appropriate beads. The hyperthermia bead project is tantalisingly close to achieving the desired outcome. We have achieved our heat output objective of 20 W/cc, at clinically acceptable magnetic field strengths and frequencies, but there are still delivery problems to overcome.

The initial work on the hyperthermia beads project resulted in the development of some unique technology for applying polymer coatings to the surface of Sirtex magnetic nanoparticles, which has resulted in a number of promising spinoff applications. The group at KCPC, headed by Professor Brian Hawkett, has a particular expertise in the application of RAFT controlled radical polymerisation to create highly stable colloidal suspensions of coated nanoparticles in all kinds of fluids. RAFT (for Reversible Addition Fragmentation chain Transfer) polymerisation technology was discovered by Australian scientists working at the CSIRO in 1998. It enables the synthesis of polymer chains with an unprecedented level of control of the molecular weight and with a high degree of functional versatility. Sirtex has negotiated a licensing deal with the CSIRO to commercially exploit certain biomedical applications of this technology.

The group at KCPC has developed world leading expertise in the application of RAFT technology to synthesise various types of coatings on nanoparticle cores, for example our magnetic nanoparticles, enabling them to form highly stable and robust particle suspensions in blood or other relatively hostile fluid media such as salty water. The KCPC group has developed and refined its expertise in this area over several years of working with Sirtex, as well as with other collaborators with interest in RAFT technology such as Dulux, Dyno Nobel and Syngenta.

There are a number of interesting applications for this nanoparticle technology that we are currently exploring, including MRI contrast agents and vehicles for improved drug delivery. Two particularly interesting developments are described below.

Enhanced treatment of solid tumour cancers by chemotherapy

by Dr Binh Pham and Dr Nguyen Pham

Solid tumours grow rapidly and do not develop a good blood supply. Chemotherapy drugs only penetrate about 70 microns from a blood vessel leaving much of a solid tumour unaffected. Thus, when chemotherapy is stopped the tumour grows again and is resistant to further chemotherapy.

Using in vitro solid tumour models, we have designed sterically stabilised nanoparticles that, when co-administered with the chemotherapy drugs, enable the drugs to fully penetrate the tumour model. We are now looking for the best in vivo options to test this system. Figure 1.

Figure 1: (a) The penetration of doxorubicin alone into a spheroid solid tumour model. Doxorubicin is one of the common drugs to treat cancer. (b) When co-administered with sterically stabilised nanoparticles.

Sirtex magnetic particles in space technology research

Sirtex magnetic nanoparticles, which were designed to make hyperthermia beads for the treatment of liver cancer, are now being used in research on navigational thrusters for mini satellites.

Using the same steric stabilisation technology that we use for biomedical applications, we have been able to stabilise the Sirtex magnetic particles in ionic liquids. Ionic liquids are of great interest for developments in space technology as many of them have exceedingly low vapour pressure and so do not evaporate off into the vacuums of space as readily as normal liquids do. When superparamagnetic nanoparticles, such as the Sirtex particles, are dispersed in a liquid in sufficient quantity, the dispersion forms ‘spikes’ in a magnetic field and the combination is termed a ferrofluid. Sirtex magnetic nanoparticles, in combination with our steric stabilisation technology, have enabled us to prepare the world’s first ionic liquid ferrofluid and attract the attention of space researchers. Figure 2 is compiled on the basis of the work of Professor Brad King, who is the Director of the Space Systems Research Laboratory at Michigan Tech. When the ‘spikes’ generated by the magnetic field (B-Field) are further subjected to an electric field (E-Field) the material from the ferrofluid would be emitted into space, causing the mini satellite to experience a thrust in the opposite direction.

Figure 2 a) An array of ILFF spikes in a vacuum. b) Close up of a single spike with no electric field. c) Spike height is enhanced by application of an electric field. d) Increasing the electric field causes emission of material from the spike.

Key personnel

Over the years there have been a number of different scientists contributing for a period with the team led by Professor Brian Hawkett. The current core members are Dr Nirmesh Jain, Dr Binh Pham and Dr Nguyen Pham.

Associate Professor Brian Hawkett did a PhD in polymer colloids in the late 70s and spent 20 years as an R&D manager in the paint, ink, adhesives and agrochemical industries. He joined KCPC as Development Manager in 1999 with the role of managing interactions with industry. His research interests are: factors governing the formation and stabilisation of colloidal dispersions and disperse phase polymerisation, especially RAFT controlled radical polymerisation.

Dr Nirmesh Jain obtained a PhD from South Gujarat University studying the micellisation behaviour of pluronic surfactants. He continued this line of study with a two year postdoc at the University of Paris. He joined KCPC in 2003 on a Dyno Nobel project on the stability of explosive emulsions. In 2006 he joined the Sirtex team at USyd and has worked on magnetic hyperthermia beads, the steric stabilisation of nanoparticles and the application of ionic liquid ferrofluids to space propulsion.

Dr Nguyen Pham did her undergraduate degree at Hanoi College of Pharmacy and worked as a medical representative for both Sanofi and Novartis before completing her masters degree at the same college. She then worked as an assistant lecturer at the College of Pharmacy before coming to Australia and Sydney University to complete a PhD in Bioinorganic Chemistry under the supervision of Professor Peter Lay. She joined the Sirtex team 12 months ago and has been working on biomedical applications of sterically stabilised nanoparticles and gallium labelled microspheres.

Dr Binh Pham obtained a PhD in disperse phase polymerisation within KCPC in 2002 and commenced work doing a postdoc on a paint based project with Dulux. At the end of this project, in 2003, she joined the Sirtex team, perfecting a membrane emulsification approach to making SIR-Spheres microspheres. She now works on our project on the biomedical applications of sterically stabilised nanoparticles. Binh has also spent time working on oral insulin with a biotech company and for ANSTO on multimodal imaging agents in nuclear medicine.

The following article was published in Michigan Tech News on 27 August 2013, it provides a further insight into the collaborative research being explored by the KCPC and Sirtex into how particles are being used in space!

Nanosatellites are smartphone-sized spacecraft that can perform simple, yet valuable, space missions. Dozens of these little vehicles are now tirelessly orbiting the earth performing valuable functions for NASA, the Department of Defense and even private companies.

Nanosatellites borrow many of their components from terrestrial gadgets: miniaturized cameras, wireless radios and GPS receivers that have been perfected for hand-held devices are also perfect for spacecraft. However, according to Michigan Technological University’s L. Brad King, there is at least one technology need that is unique to space: “Even the best smartphones don’t have miniaturized rocket engines, so we need to develop them from scratch.”

Miniature rockets aren’t needed to launch a nanosatellite from Earth. The small vehicles can hitchhike with a regular rocket that is going that way anyway. But because they are hitchhikers, these nanosats don’t always get dropped off in their preferred location. Once in space, a nanosatellite might need some type of propulsion to move it from its drop-off point into its desired orbit. This is where the micro rocket engine comes in.

For the last few years, researchers around the world have been trying to build such rockets using microscopic hollow needles to electrically spray thin jets of fluid, which push the spacecraft in the opposite direction. The fluid propellant is a special chemical known as an ionic liquid. A single thruster needle is finer than a human hair, less than one millimeter long and produces a thrust force equivalent to the weight of a few grains of sand. A few hundred of these needles fit in a postage-stamp-size package and produce enough thrust to maneuver a nanosatellite.

These new electrospray thrusters face some design challenges, however. “Because they are so small and intricate, they are expensive to make, and the needles are fragile,” says King, the Ron and Elaine Starr Professor of Mechanical Engineering-Engineering Mechanics. “They are easily destroyed either by a careless bump or an electrical arc when they’re running.”

To get around the problem, King and his team have developed an elegant strategy: eliminate the expensive and tedious microfabrication required to make the needles by letting Mother Nature take care of the assembly. “We’re working with a unique type of liquid called a ferrofluid that naturally forms a stationary pattern of sharp tips in the liquid surface,” he says. “Each tip in this self-assembling structure can spray a jet of fluid just like a micro-needle, so we don’t actually have to make any needles.”

Ferrofluids have been around since the 1960s. They are made of tiny magnetic particles suspended in a solvent that moves when magnetic force is applied. King illustrates with a tiny container holding a ferrofluid made of kerosene and iron dust. The fluid lies flat until he puts a magnet beneath it. Then suddenly, the liquid forms a regular series of peaks reminiscent of a mountain range or Bart Simpson’s haircut. These peaks remain perfectly stable despite vigorous shaking and even turning the container upside down. It is, nonetheless, completely liquid, as a finger-tip touch proves undeniably. When the magnet is removed, the liquid relaxes to a perfectly flat surface.

King’s team was trying to make an ionic liquid that behaved like a ferrofluid when they learned about a research team at the University of Sydney that was already making these substances. The Sydney team was using magnetic nanoparticles made by the life-sciences company Sirtex, which are used to treat liver cancer. “They sent us a sample, and we’ve used it to develop a thruster,” King said. “Now we have a nice collaboration going. It’s amazing that the same technology used to treat cancer can also function as a micro rocket for spacecraft.”

King’s first thruster is made of a one-inch block of aluminum containing a small ring of the special fluid. When a magnet is placed beneath the block, the liquid forms a tiny, five-tipped crown. When an electric force is then applied to the ferrofluid crown liquid jets emerge from each point, producing thrust. “It’s fascinating to watch,” King says. “The peaks get taller and skinnier, and taller and skinnier, and at some point the rounded tips instantly pop into nano-sharp points and start emitting ions.”

The thruster appears to be almost immune to permanent damage. The tips automatically heal themselves and re-grow if they are somehow damaged. King’s team has already demonstrated its self-healing properties, albeit inadvertently. “We accidentally turned the voltage up too high, and the tips exploded in a small arc,” King says. While this would spell death for a typical thruster, “A completely new crown immediately formed from the remaining ferrofluid and once again resumed thrusting.”

Their thruster isn’t ready to push a satellite around in orbit just yet. “First we have to really understand what is happening on a microscopic level, and then develop a larger prototype based on what we learn,” King said. “We’re not quite there yet; we can’t build a person out of liquid, like the notorious villain from the Terminator movies. But we’re pretty sure we can build a rocket engine.”

King has applied for a patent on the new technology. The research is funded by the Air Force Office of Scientific Research.

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